The overall goals of this project are to study aspects of a) the mechanism of action of thyrotropin (TSH) and thyroid stimulating immunoglobulin (TSI) on the thyroid gland, b) the clinical value of the measurement of TSI bioactivity in serum. It is proposed to study the following specific subjects: 1) Biological significance of TSH stimulation of thyroid cell ADP-ribosylation. ADP-ribosylated thyroid proteins will be examined for their subcellular localization and electrophoretic mobility. The effect of inhibitors of ADP-ribosylation reactions on TSH stimulated thyroid cell functions will be examined. 2) Mechanism of inhibition of iodide of TSH activation of thyroid adenylate cyclase: The functional activity of adenylate cyclase complex in thyroid cells previously treated with iodine will be studied. 3) Mechanism of desensitization of the cAMP response to TSH stimulation: Functional activity of the adenylate cyclase complex will be examined in thyroid cells desensitized to TSH. The interrelationship between the TSH desensitization process and RNA transcrption, protein translation, and DNA synthesis will be examined. 4) In vitro action of thyroid stimulating immunoglobulin (TSI). Aspects to be studied include the effect of TSI on ADP-ribosylation, protein, RNA and DNA synthesis; the requirement for TSI internalization; and TSH species specificity. 5) Clinical value of the measurement of serum TSI bioactivity. The following will be examined: a) prediction of relapse of hyperthyroidism following therapy, b) prediction of the development of neonatal hyperthyroidism; c) diagnosis of euthyroid Graves' of ophthalmopathy; d) the effect of therapy of hyperthyroidism in Graves' disease on TSI bioactivity, e) the incidence of TSI bioactivity in the serum of patients with thyroid disease other than Graves' disease. 6) Studies on the bioactivity of TSH. high-performance liquid chromatography will be used to study the bioactivity of TSH subunit recombinants. The importance of TSH oligasaccharides in the expression of TSH bioactivity will be examined.